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Philanthropic first-responders support COVID-19/Pandemic Research Fund

Facing the biggest public health crisis of our time, the UMass Chan Medical School* philanthropic community responded rapidly, and significantly, to fund important research projects that are making a difference in the trajectory of the COVID-19 pandemic.

These projects are contributing to a better understanding of how the virus SARS-CoV-2 infects cells, replicates in cells and interacts with the human immune system. Much of the science revealed in these early studies is now targeting potential new therapies for people infected with the virus, which are a vital clinical need.

“What we’ve seen over the past year is translational research at its best,” said Kate Fitzgerald, PhD, the Worcester Foundation for Biomedical Research Chair, professor of medicine, vice chair of research for the Department of Medicine, director of the Program in Innate Immunity and chair of the review committee that evaluated proposals for funding from the COVID-19/Pandemic Research Fund. “Basic research discoveries illuminate potential therapeutic targets for focused development, while clinical studies feedback real-time results.”

Pilot grants from this fund to leverage their experience across disciplines and to jump-start promising early ideas. The labs did not duplicate efforts already underway; rather, their focus has been on filling knowledge gaps. (See this report to fund donors produced in April 2021 for summaries of all 13 programs.)

“The progress these investigators, and others, are making is remarkable,” Dr. Fitzgerald said. “And it’s made possible by the support of our donor community, who are dedicated to bettering public health by funding early research. For that, we are so thankful.”

Among the milestones achieved from the pilot grants as of August 2021 are two peer-reviewed publications and several drug candidates identified that show significant effectiveness against the virus in animal models.

Fiachra Humphries, PhD, an instructor of medicine working in the Fitzgerald lab in the Department of Medicine, launched a project to prompt an immune response against SARS-CoV-2. The lab sought to kick-start an innate immune pathway to block the virus from replicating once it had infected a cell. Pilot grant funding enabled Dr. Humphries to complete the safety training needed to work with pathogens like SARS-CoV-2, and to engineer mouse models that express the human receptor the virus exploits to infect lung cells.

asterisk yellow 100.png After a series of experiments done in collaboration with scientists at the pharmaceutical company GlaxoSmithKline, Dr. Humphries and colleagues reported stunning findings in a paper published in Science Immunology.

The novel compound they tested, called diABZI-4, “inhibited SARS-CoV-2 replication in lung epithelial cells. Administration of this compound intra-nasally before or even after virus infection conferred complete protection from severe respiratory disease in the mice infected with SARS-CoV-2.”

Subsequent cell studies showed that diABZI-4 was able to stimulate an innate immune response which is believed to have protected the mice against the disease. Further pre-clinical studies of the compound are now underway, in hopes of advancing diABZI-4 for potential development as an anti-viral drug.

Another promising therapeutic approach is being taken by Celia Schiffer, PhD, the Gladys Smith Martin Chair in Oncology, and Paul Thompson, PhD, both professors of biochemistry & molecular pharmacology. They began by screening thousands of molecules previously developed for other programs to see if those molecules would block the function of two proteases—enzymes in the host cell that the SARS-CoV-2 virus utilizes to make more copies of itself and eventually cause disease.

Using high-throughput robotic systems, the team identified a dozen small molecules that showed potential to block the proteases. Upon further testing, the team has homed in on one molecule that was shown to attach itself to the proteases in nearly all cases. Work continues to optimize the chemical structure of that molecule so it will effectively bind within a key zone, known as the “binding envelope.” The Schiffer lab had previously characterized that zone as the optimal spot for a protease inhibitor to bind and block the proteases from doing their work.

asterisk yellow 100.png Early data from a mouse model study done in collaboration with the Fitzgerald lab is very encouraging, and the research team continues to optimize its approach and prepare for a larger pre-clinical study.

SARS-CoV-2 is a single-stranded RNA virus that carries 27 genes, and much research has focused on the viral genes and the proteins they encode. Sean Ryder, PhD, professor of biochemistry & molecular pharmacology, used pilot grant funding to take a different approach: to analyze structural sections of the virus for weak spots that could be targeted by new drugs to block viral replication.

The study was based on data mining of more than 20,000 viral sequences that had been characterized and uploaded to public data bases from scientists around the world. Through that analysis, Dr. Ryder found two potential target regions along the RNA strand that are consistent across many viral variants. Those spots could become targets for drugs specifically designed to bind there, and by doing so, block viral replication after SARS-CoV-2 infects cells.

asterisk yellow 100.png Dr. Ryder and his colleagues recently reported these initial findings in the journal Evolutionary Bioinformatics.

The research continues, with the Ryder lab working on a new round of data mining based on tens of thousands of additional SARS-CoV-2 variant sequence data collected globally in recent months.

Pilot grant funding for the lab of Neal Silverman, PhD, professor of medicine in the Division of Infectious Diseases and Immunology, is focusing on epithelial cells in human lungs, since COVID-19 does the most damage in the respiratory system. Dr. Silverman theorized that once the virus infects a cell, a particular lipid receptor on the cell’s surface could play a role in helping the virus replicate. That lipid receptor helps channel lipid molecules into cells for normal cell functions. However, SARS-CoV-2 also needs lipids for various stages of its replication process.

Dr. Silverman’s team conducted a series of experiments using compounds known to clog or block the function of this lipid receptor. Early results showed that lung cells infected with SARS-CoV-2 had lower levels of viral replication when the lipid receptor was blocked. With that positive outcome, Dr. Silverman repeated the experiments using other viruses and found similar results, indicating that shutting down the lipid tunnel could have a broader impact as an anti-viral compound.

asterisk yellow 100.png Work continues with plans to test the compound in a COVID-19 mouse model.

James Munro, PhD, associate professor of microbiology & physiological systems, has used pilot grant funds to visualize the structure and motion of the SARS-CoV-2 spike protein, which is the tip of the viral spear for infection. The Munro lab is using an advanced imaging system called single molecule fluorescence spectroscopy, which can focus at the molecular level to capture live images of the moment of first contact between the spike protein and the cell surface receptor it targets.

The spike protein changes its shape as it prepares to bind to a cell wall and begin the process of infection. Dr. Munro analyzed a group of antibodies, including those now used to treat COVID-19 patients, and verified the areas along the spike protein where they bind. That structural information may lead to better designs for both antibodies and next-generation vaccines.

asterisk yellow 100.png A paper describing the findings is now pending review.

*As of Sept. 7, 2021, which is in the FY22 fiscal year, UMass Chan Medical School is now UMass Chan Medical School thanks to a transformational gift.